Prevalence and predictors of difficult vascular anatomy in forearm artery access for coronary angiography and PCI

Transradial access has established as preferred access for cardiac catheterization. Difficult vascular anatomy (DVA) is a noticeable threat to procedural success. We retrospectively analyzed 1397 consecutive cardiac catheterizations to estimate prevalence and identify predictors of DVA. In the subclavian-innominate-aortic-region (SIAR), DVA was causing failure in 2.4% during right-sided vs. 0.7% in left-sided forearm-artery-access (FAA) attempts (χ2 = 5.1, p = 0.023). Independent predictors were advanced age [odds ratio (OR) 1.44 per 10-year increase, 95% confidence interval (CI) 1.15 to 1.80, p = 0.001] and right FAA (OR 2.52, 95% CI 1.72 to 3.69, p < 0.001). In the radial-ulnar-brachial region (RUBR), DVA was causing failure in 2.5% during right-sided vs. 1.7% in left-sided FAA (χ2 = 0.77, p = 0.38). Independent predictors were age (OR 1.28 per 10-year increase, 95% CI 1.01 to 1.61, p = 0.04), lower height (OR 1.56 per 10-cm decrease, 95% CI 1.13 to 2.15, p = 0.008) and left FAA (OR 2.15, 95% CI 1.45 to 3.18, p < 0.001). Bilateral DVA was causing procedural failure in 0.9% of patients. The prevalence of bilateral DVA was rare. Predictors in SIAR were right FAA and advanced age and in RUBR, left FAA, advanced age and lower height. Gender, arterial hypertension, body mass, STEMI and smoking were not associated with DVA.

www.nature.com/scientificreports/ artery, proximal ulnar artery and distal brachial artery. In this region, radioulnar loops, radial artery stenosis, radial/brachial tortuosity, and atypical arterial branching (e.g., high origin of radial artery) have been identified as potential obstacles previously 2,3 . Secondly, the guidewire must transverse the subclavian-innominate-aortic region (SIAR), encompassing the proximal subclavian artery, the proximal innominate artery, and the transition into the aortic arch, before reaching the ascending aorta and finally the coronary ostia. In this region, subclavian tortuosity, high atherosclerotic burden, subclavian artery occlusion, innominate artery stenosis and aortic arch elongation have been described as anatomical substrates for complex procedures in earlier studies 4,5 . Figure 1 shows representative examples of DVA encountered in our institution during the study period.
Although some technical solutions have been proposed to overcome difficult vascular anatomy 6,7 , DVA is still estimated to be the reason for procedural failure in 2-10.8% of cases [8][9][10] , and one of the main reasons for crossover to the riskier TFA as has been proven 11 . Besides technical challenges 12 , DVA is also associated with a higher occurrence of vascular complications at the arm, e.g., arterial perforation, arterial dissection, hematoma formation or compartment syndrome 13 .
While the prevalence of vascular variants in right SIAR has been the subject of numerous studies 6,10,14 , data on vascular obstacles in RUBR or at the left arm in general is sparse. This contrasts with an increasing openness for alternative access sites (e.g., left distal radial artery, ulnar artery, brachial artery) to avoid TFA 15,16 .
The main objective of our study was to investigate the prevalence of 1st degree and 2nd degree DVA in RUBR and SIAR for the left and right arm respectively (see Table 1). Another aim was to estimate the prevalence of bilateral DVA necessitating crossover to TFA in a real-life clinical setting. Beyond that, we set out to identify clinical risk factors for difficult vascular anatomy, to provide patient-tailored preoperative planning in future  Technical considerations. In our standardized approach, operating physicians were urged to attempt forearm artery access (FAA) for cardiac catheterization whenever possible. Ultrasound-guided arterial puncture followed by standardized forearm angiography including the ipsilateral distal brachial artery was mandatory after sheath insertion (Glidesheath Slender Terumo, 6-French or 7-French, Administration of weight-based dose of unfractionated heparin (50 IU/kg). Guidewires were advanced under continuous fluoroscopic guidance and retrograde angiograms were obtained when necessary. The choice of forearm artery and side used in an individual patient was at the discretion of the operator. By institutional policy, left FAA was mandatory in patients with left internal mammary bypass graft. Arterial access sites included the distal radial artery in the anatomical snuffbox, the proximal radial artery, the ulnar artery, and the anterior interosseous artery. Primary TFA was only performed if inaccessibility of all major forearm arteries was evident from patient history (e.g., dialysis shunts on both forearms) or previous angiographies. In case of failure to complete cardiac catheterization via the primarily chosen forearm artery, operating physicians were principally required to crossover to another artery on the ipsilateral or contralateral forearm by institutional policy ("forearm-only-strategy"). During the study period, cardiac catheterization was performed by six interventional cardiologists with a record of at least 300 ultrasound-guided forearm artery cannulations each. After each case of cardiac catheterization, operating physicians documented the presence and the severity of DVA.

Difficult vascular anatomy.
After FAA for cardiac catheterization was established, vascular anatomy of arm arteries was assessed functionally regarding successful guidewire/-catheter passage. A total of three categories were defined (see Table 1). The prevalence of 1st and 2nd degree DVA was assessed in four regions of interest: RUBR and SIAR of the left and right arm respectively. Only cases, where at least the guidewire reached the region of interest, were included to determine the prevalence of DVA, e.g., if coronary access failed due to a vascular obstacle in right RUBR, this was counted as 2nd degree DVA in right RUBR but not included to determine the prevalence of DVA in right SIAR.
To meet the assumption of independence, as far as possible in a clinical setting, only the first access attempt was included to determine the prevalence of DVA, i.e., if right TRA failed due to e.g., a radial loop and crossover to left TRA was necessary, observations from the left arm were not included in the statistics.
Patients, who had left and right FAA either in the same or a subsequent procedure during the study period, were included for intraindividual comparison analysis to further investigate the association between leftvs. right-sided FAA and DVA.
Statistical analysis. For statistical analysis, continuous variables were summarized as mean ± standard deviation (SD) and median ± interquartile ranges ([IQR]) for non-normally distributed variables. QQ-plots and the Shapiro-Wilk test were used to assess normality. Rates of interest were reported with 95% confidence intervals respectively. We analyzed the prevalence of 1st -and 2nd degree DVA for each anatomical location respectively. Pearson's chi-square test was used for comparison of dichotomous data.
Predictors of DVA, encompassing the presence of either 1st or 2nd degree DVA, were evaluated separately for RUBR and SIAR. Clinical predictors were identified as follows: variables that were significant in univariate analysis were included in subsequent multivariable analysis to find independent predictors of DVA. A generalized estimating equations (GEE) binomial model with a logit link and an exchangeable correlation structure was applied to account for correlated observations since some patients had more than one procedure within the study period.
For comparison of paired proportions, McNemar's exact test was used and odds ratios with central 95% confidence intervals were reported. For each patient, the chronologically first evaluation of DVA was included for each arm respectively. Time spans between intraindividual evaluations were reported as mean ± standard deviation. A two-sided p-value < 0.05 was considered significant.
Due to technical failure, data for estimated glomerular filtration rate was missing in two procedures. Missing data was classified as missing at random and listwise deletion was applied where necessary. All statistical analyses were carried out with Python 3.9 and R 4.0.3. Ethics committee approval was waived for this retrospective analysis (Ethics committee Friedrich-Alexander-University Erlangen, Erlangen, Germany, Number: 20-548_1-Br). All experiments were performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants as part of the admission contract, which is signed by any patient of our hospital. In this contract, the patients agree, that an anonymized retrospective analysis of their data is allowed. In RUBR, 2nd degree DVA was observed in 2.5% of procedures with right FAA and 1.7% of procedures with left FAA (χ 2 = 0.77, p = 0.38, power = 0.19). 1st degree DVA was more prevalent in left RUBR compared to right RUBR (11.6 vs. 4.1%, χ 2 = 23.2, p < 0.001). 2nd degree DVA in SIAR was observed in 2.4% of procedures with right FAA and in 0.7% with left FAA (χ 2 = 5.1, p = 0.023). 1st degree DVA was more frequently observed in right SIAR compared to left SIAR (13.7 vs. 7.1%, χ 2 = 14.5, p < 0.001). Table 2 summarizes the prevalence of DVA during primary FAA in the procedures under review. During a total of 40 transulnar access (TUA) attempts, including secondary and tertiary access attempts, 2nd degree DVA with respect to the ulnar artery was never reported and was also not observed when 2nd DVA prevented ipsilateral TRA (n = 3) in the first place.
DVA in RUBR was observed in 136 out of 1328 procedures (10.2%). In procedures, where 1st or 2nd degree DVA in RUBR was observed, patients were significantly older (74. 6 Fig. 2). Table 2. Prevalence of difficult vascular anatomy (DVA) at the primary FAA site. In 1328 procedures successful sheath insertion allowed for adequate assessment of DVA in the radial-ulnar-brachial region (RUBR). In 1306 procedures, DVA could be adequately assessed in the subclavian-innominate-aortic region (SIAR).  Fig. 3).
To further evaluate differences in the prevalence of DVA between both arms, patients who had left and right FAA either in the same or a subsequent procedure during the study period, were included for intraindividual comparison. In RUBR, DVA could be evaluated bilaterally in 30 patients during the same procedure and in 95 patients during a subsequent procedure. In 52 cases the same operator evaluated DVA in RUBR bilaterally and the average time span between evaluations was 31 ± 52 days, with a maximum of 273 days. DVA was significantly more prevalent in left RUBR (OR 2.7, 95% CI 1.1 to 7.6, p = 0.029) while no statistically significant differences could be found for 2nd degree DVA (OR 1.0, 95% CI 0.33 to 3.1, p = 1.0).
In SIAR, DVA could be evaluated bilaterally in 13 patients during the same procedure and in 94 patients during a subsequent procedure. In 34 cases the same operator evaluated DVA in SIAR bilaterally and the average time span between intraindividual evaluations was 36 ± 55 days, with a maximum of 273 days. DVA (OR 4.0, 95%   Tables 3 and 4.

Discussion
Our retrospective single-center analysis of an all-comer cohort of patients, showed that the prevalence of DVA was relevant, ranging from 0.7 to 2.5% depending on the anatomical location. To our knowledge, this is the first study to quantify the prevalence of DVA especially in RUBR and separately for both arms. 2nd degree DVA was more prevalent in RUBR compared to SIAR despite not reaching statistical significance (2.0 vs. 1.5%). This is surprising, since most of previous studies exclusively focused on the assessment of DVA in SIAR. For instance, Rigatelli et al. observed a "hostile subclavian artery", which could not be passed despite a sophisticated mother-and-child technique, in 2.1% of cases 6 . Studies exploring vascular variants in RUBR, predominantly focused on visual rather than functional assessment 5,13 or almost exclusively focused on right RUBR 4,17 . The particular interest in vascular variants in SIAR might be attributed to the fact that abnormalities in SIAR, even in the less severe form of 1st degree DVA, can significantly hinder subsequent guidewire/guide catheter manipulation and is even associated with vascular injuries and thromboembolic stroke due to excessive device manipulation 6,9 . This is in stark contrast to 1st degree DVA in RUBR, which once this anatomical region is passed, does not subsequently interfere with procedural success in our experience. However, our data indicates that DVA in RUBR must be taken seriously. In this context, it is particularly noteworthy that 2nd degree DVA was never observed during TUA but only during TRA. This resonates with previous studies, which reported that the ulnar artery, as the natural continuation of the brachial artery, following a straight course at the forearm without excessive tortuosity, loops or unfavorable branching angles represents an at least equivalent alternative  www.nature.com/scientificreports/ to TRA 18 . However, the proportion of transulnar access attempts in our study was insufficient to provide generalizable conclusions. According to our knowledge, the prevalence of FAA failure due to bilateral 2nd degree DVA has not yet been systematically studied. Previous studies gave estimates of approximately 8% for bilateral anatomical variants focusing on angiographic descriptions of vascular variants rather than functional aspects 5 . With our quasi-allcomer-design and a high primary FAA rate of 97.6%, we are confident to sufficiently estimate the prevalence of bilateral 2nd degree DVA at 0.9%. The probability of encountering 2nd degree DVA at the contralateral arm, when 2nd degree DVA caused FAA failure at the ipsilateral arm, was found to be 15.4%. This indicates that DVA possibly clusters in individual patients, which was previously presumed by others 5,6 . However, this also implies that the presence of unilateral 2nd degree DVA should not discourage operators from subsequent FAA attempts at the contralateral arm before crossover to TFA.
The pathophysiology of DVA and its clinical predictors are not yet fully understood. In our study, independent predictors of DVA in RUBR were advanced age, lower height, and left FAA. In SIAR, independent predictors were limited to advanced age and right FAA. These findings concur well with previous studies, which identified advanced age and short stature as predictors for both severe tortuosity of the right subclavian artery 10 and TRA failure 9,19 . In contrast to a previous study by Cha et al. 10 , which identified female gender and higher body mass index as predictors of severe tortuosity of the right subclavian artery, female gender and higher BMI were not found to be independent risk factors of DVA in our study population. This observation is of high importance for clinical practice, since both female sex and obesity are linked with increased risk of bleeding complications during transfemoral access 20,21 .
In multivariable analysis, the choice of access site (left vs. right FAA) stood out as the single most important predictor for DVA both in RUBR and SIAR. While earlier studies found that severe tortuosity of the subclavian artery and vascular variants in general were more prevalent at the right arm 5,6 , the access site was mostly not taken into account when DVA was analyzed in previous studies 10,17 .
Our results from intraindividual comparisons provide further evidence that DVA in general and 2nd degree DVA is more frequently found in right vs. left SIAR. These functional results match well with the aforementioned, angiographic observations that severe tortuosity of the subclavian artery is more prevalent at the right compared to the left arm 5,6 . The fact that both DVA and 2nd DVA were less prevalent in left SIAR might affect access site preferences for FAA in future procedures.
The results from intraindividual comparisons also further confirmed that DVA but not 2nd degree DVA was more frequently found in left vs. right RUBR. The higher prevalence of DVA in left vs. right RUBR was mainly driven by a higher prevalence of 1st degree DVA (see Table 2). This could be attributed to the fact that the left forearm is angled inwardly for operator comfort after left FAA is established. Inward angulation of the forearm with concomitant elbow flexion might lead to coiling of the radial artery at the brachioradial junction possibly impeding guidewire advancement. Therefore, it might be useful to bring the left arm into a neutral position when DVA is encountered, to facilitate guidewire passage. However, this was not the objective of our retrospective analysis and further experimental studies are needed to estimate a potential benefit. The prevalence of DVA was not significantly different in STEMI cases, neither in RUBR nor SIAR. This indicates that fixed anatomical variants, rather than interventional technique or the presence of vasospasm, are the cause of DVA.

Limitations.
The main limitations of our study encompass a single-center cohort, a low proportion of female patients in the study cohort and a nonrandomized study design. Additionally, it cannot be ruled out that information from previous procedures influenced the operator's choice of primary access site, potentially leading to selection bias.